AGBT 2021: A Spatial Foundation

I'll call it now -- the big buzz at this year's AGBT will be around spatial profiling.  Trust me, it's not just a hunch.  The two current players in the field -- nanoString and 10X Genomics -- both have significant presence in the virtual conference.  Don't be surprised to see more players on the field -- just sayin'

PacBio With SoftBank's $900M: How Might TheyWork?

Pacific Biosciences continued its roll of successful business development, snagging $900M from Japan's SoftBank two weeks ago.  Combined with a recent secondary stock offering and a major deal with Invitae, PacBio has gone from their self-proclaimed near-derelict status during the Illumina acquisition attempt saga to rolling in cash.

More Details on 10X's Sample Profiling Trident

10X Genomics had an online event Wednesday called Xperience (as far as I could tell no Jimmy Hendrix music was used, a missed opportunity!) to lay out their development roadmap.  This largely paralleled the presentation given at J.P. Morgan, but there were a few new bits and of course much more technical detail to whet the appetites of scientists -- and judging from a number of very positive tweets I saw today they were successful in that goal. Some of the 10X management was kind enough to walk me through the deck earlier this week as well as permission to borrow images from it, so this summary is based on that as well as watching the presentation.  While their name is 10X, the company emphasized progress on three axes: scale, resolution and access and that progress across the three different platforms. 

Could I See Myself at J.P. Morgan?

There's a question that others pop my way pretty much every year around J.P. Morgan: would I ever attend myself?  I'll confess it never occurred to me before I was asked, but that isn't necessarily a deal breaker.  I foolishly didn't attend AGBT until 2013 when Alexis Borisy (then CEO of Warp Drive) suggested I go -- I think it was mostly because he thought it was a good investment and probably only secondarily to keep me off the ski slopes for a week -- I shattered my knee just after AGBT 2012 ended.  It's an interesting but complex question which I will answer one way here, but freely admit that over coffee I could be nudged one way or the other.

Why I Hated One Genapsys Slide

I claimed in my Miscellanea piece that I was one post away from being done with J.P. Morgan -- oops, forgot I had drafted a minor screed on data display which I'll push out before the last piece - particularly since I hinted I would be taking Genapsys to task on this subject.  Unexpectedly good timing too: maybe new Genapsys CEO Jason Myer's first big initiative can be to fix this plot!

J.P. Morgan: Miscellania

Before J.P. Morgan is truly a month ago I should clean up some loose ends as a penultimate post driven by this year's virtual conference (the last post isn't exactly time sensitive).  In contrast to the single company focused items that preceded it, this is a grab bag of minor observations and notes.

J.P.Morgan: NanoString

Almost done with my J.P. Morgan summaries -- this will be the last focused on a specific company: nanoString.   They wish to emphasize that they are becoming the company for spatial analysis of DNA, RNA and proteins in biological samples.  They also want us to differentiate that space into two segments: profiling and imaging.  Profiling gathers spatial information from regions of multiple cells; imaging in their lingo covers spatial techniques with single cell or subcellular localization. In both cases nanoString is betting heavily on oligo-tagged antibodies to enable deep multiplexing of protein detection to be integrated with RNA and DNA detection.  

J.P. Morgan: Genapsys

Genapsys' J.P. Morgan presentation by CEO Hesaam Esfandyarpour focused on their story of delivering a compact sequencer based on electronic detection that offers low capital, low cost sequencing.  There were two bits of specific product news, but mostly general painting of a rosy picture.  

J.P. Morgan: PacBio

PacBio CEO Christian Henry’s presentation at J.P. Morgan wasn't rich in technical specifics. But he gave a very bullish portrait of a company aiming for the stars.  A conflict reminder: he’s a member of the Board of the Strain Factory that employs me, though I haven’t yet had the pleasure of meeting him.

The biggest news is a broad partnership with Invitae four clinical human genome sequencing. The only specific here is that this is not the whole enchilada; platform development will take place both within the Invitae collaboration and outside it. What might that development be?

Between Henry’s comments in the Q&A and a few info crumbs on slides there will be pushed to further tune all the canister. Her mentioned efforts on dyes and further improving SMRTcell loading efficiency. There was chatter on Twitter about an overdue update to improve HiFi yields.

Henry talked of the importance of increasing ZMW packing, but gave no specifics other than to suggest this is more "development" than "innovation" -- this was in response to a question asking if technical breakthroughs are required.   But we are left wondering on a timetable as well as what the next density might be; four-fold to 32M  wouldn’t be surprising on naïve geometry grounds. 

I suspect a huge area of joint effort with Invitae will be to automate HiFi library production. The current protocol is long, manual and labor intensive - not at all appealing for lease scale clinical use. How much of that will be retained as proprietary to Invitae will remain to be seen.  Henry claims that the Invitae effort will be separate but coordinated with existing development efforts; prior plans have not been shelved or diverted to support Invitae. A major software effort to support clinical operations is a given. PacBio has separate workflows for SNP and SV calling and those must be integrated and a clinician-friendly report generated. 

Henry believes that the new Sequel IIe will be the dominant product shipped going forward.  It will be interesting to see which of the older workflows PacBio updates and moves into the on-board compute.  For example, if you want to call methylation you must export BAM files with kinetics data, which are predicted to be five-fold fatter.  If the methylation calling happened on board, then that extra processing and extra data would be eliminated.  

Similarly, workflows such as microbial assembly are still based around Continuous Long Reads (CLR).  Henry didn't mention CLR once (I think).  While I doubt they would ever dump it altogether like they did Strobe Reads, it would seem likely that it won't get much attention.  Oxford Nanopore can beat them on very long reads and their single molecule accuracy is much higher; far better to focus on the CCS/HiFi reads where PacBio can deliver much higher accuracy.  It will be interesting to see if PacBio pushes the HiFi fragment read length longer.  On the one hand it will be more challenging to work with longer fragments and to routinely get enough circuits around them to deliver HiFi quality data.  Twenty five kilobases is a nice size for many applications, but there will always be incremental value for going to thirty or forty or beyond.

In response to a question about $1000 genomes, Henry described it as "just a number" around "where it makes sense" in high throughput applications.  He says the Invitae collaboration will be able to drive prices below $1000.  But he also pushed the idea that a PacBio genome is a truly clinical grade genome and has higher value than genomes produced on other platforms.  He argued that this higher value, in terms of higher diagnostic yield for rare diseases, will be more attractive to payers and that there will be a net benefit to the healthcare industry by ending diagnostic odysseys sooner.   He vowed to continue generating "diagnostic proof statements" to provide evidence to support the higher value claim.

Should be interesting to watch, particularly if you have a front row seat in front of a Sequel IIe,

J.P. Morgan: 10X Genomics

As I attempt to collate various incomplete thoughts about the J.P. Morgan presentations I have read and listened to from genomics instrument shops, one thing stands out about 10X Genomics: they actually announced new gadgets and kits! I should thank the company for supplying the slides after I snarked on Twitter about how they weren't archived in the J.P. Morgan webcast -- but now it is there.  So either my eyes failed again or I had a personal IT failure (I think the website doesn't like iOS and I may have forgotten that).  The slides were presented by CEO Serge Saxonov

JP Morgan: Illumina

Illumina presented at J.P. Morgan on Monday, reminding us that they aren't just a sequencing instrument company but an interlocking set of businesses focused on genomics. CEO Francis deSouza spent much of his time discussing the Grail acquisition and some of the other ways in which Illumina is pushing rapidly to become an essential part of clinical medicine, but there was one slide on future improvements to sequencing technology and a few on the lineup of existing sequencers.  Reminder: I'm working off public sources, as during the day we work closely with Illumina and they even sunk some serious cash into my employer last May.

J.P. Morgan 2021

The J.P. Morgan Healthcare Conference has started this morning in virtual form, so I'd really better get this draft cleaned up and out (indeed, Roche is presenting as I hurriedly type, though about pharma not diagnostics).  2021 already feels like a darker continuation of 2020, between the appalling putsch attempt in my nation's center of government last Wednesday and the still buggy roll-out of the coronavirus vaccine.  As I noted in my piece on the Oxford Nanopore Community Meeting, the many disruptions of 2020 make grading the progress of companies essentially impossible: many were disrupted by lockdowns, supply chain issues and the general distraction from the year of doomscrolling. 

Advent of Code vs. FizzBuzz

A bunch of coding types at the Strain Factory participated in The Advent of Code, a clever 24-day set of programming challenges that runs each year before Christmas.  Each day a new two=part programming challenge was posted.  Technically it is a speed contest, but you won't find me on the public leaderboard as I'm not nearly quick enough to ever rate a point there.  One of my  major official activities last month was contributing towards screening candidates for three different computational positions, one of which we threw open to general data science experience.  As a result, I've been thinking far too much about the FizzBuzz problem and my prejudices towards it.

Peri-New Year Nanopore Playing

Ever since the community meeting I've been toying with an idea,  then never quite trying to code it.
 So on New Year's Eve I started getting the dataset together and reducing it to a bunch of dataframes, and today I pushed that a bit further and started graphing some of it.  It's very much a rough project -- some of the dataframes have some issues I'm still chasing down with redundant data not being initially collapsed, but I think the data is accurate.  I also think I have my conventions consistent -- at one point confused myself into inverting the labels on the plots!  In other words, ApG would be labeled GpA -- not good! There's already some intriguing patterns, which are presumably the sort of signal tools like Medaka use to polish assemblies from FASTQ data aligned to draft references.

Nanopore Community Meeting: Progress Despite the Pandemic

I realized a few Oxford Nanopore announcements too late that I should have tried to log all their predictions with a date made so I could track carefully any delays or quiet disappearances from the new feature lineup.  If I had done that, this year would have presented an even worse conundrum: how do you score progress in a year of constant disruptions?  Like many companies in the sequencing field, at least some of that disruption has been a diversion of attention and resources to fighting the pandemic.  For ONT that is largely supporting the ARTIC viral genome sequencing and also developing LamPORE diagnostics.

BGI Floats Idea of Tape-Based Sequencer

I reported on the AGBT 2020 final talk a few centuries ago -- or at least it seems like that given how quickly the world went to hell just after that -- by BGI in which Rade Drmanac showed off a system which I described as a deconstructed sequencer -- an integrated set of plate handling robots, liquid handlers and imagers which dipped the slides into reservoirs of reagents instead of flowing them through a flowcell.  Now BGI has a preprint on BioRxiv which takes this idea a bit further, changing out the reagent tanks for a polymer film on which a thin layer of reagent is distributed, which is then pressed gently against the slide surface to deliver the reagent to the DNA Nanoball (DNB) array.  The preprint is filled with eye-popping numbers -- Petabase sequencing!

PacBio's Renewed Energy

When confronted by antitrust regulators last year, the core thesis of Illumina and Pacific Biosciences was that PacBio could not survive as an independent company.  After giving up on the merger, PacBio decided to dispute their own thesis -- and seem to be succeeding so far.  As highlighted at their recent "Global Summit" meeting, they have a new CEO, new financing and a burnished product offering.

Bioinformatics Exercise: Gene-Specific Ser Codon Usage

I saw a provocative abstract in PNAS about the usage of serine codons in E.coli that triggered the "this could make an interesting student exercise" (for my prior effort, see: Exercise: A Sequence Signature for Transcription-Translation Coupling in Bacteria?).  The paper is behind a paywall (though a relatively cheap one at $10) so I haven't actually read the paper, but the purposes here that isn't really a problem -- I'm not going to critique the paper, but just use the concept as a springboard.

Bionano Genomics: A Belated Update

Back before I can remember -- as in January of this year -- I wrote a piece on the challenging situation of BioNano Genomics.  I got an important detail wrong in that piece, missing some important fundraising, but in general from the point-of-view I took I thought it was a decent piece, meant to convey the challenge of a really amazing technology having its original market disappear.  Some commenters took strong exception to the piece and suggested I had not-so-pure motives for writing it.  They're wrong -- but at AGBT I got a chance to learn more about the company's new direction and how I hadn't been looking at things quite appropriately.  I should have written it up there, but working on a response to the pandemic started taking over my life and I let time slip away.  Preparing crow to be eaten also tends to be procrastinated.  But here, finally, is a re-look at the company (and, I drafted this over a month ago and never finished -- the procrastination drags on...)

I was a bit nervous strolling into the BioNano Genomics booth at Marco Island.  Maybe they were the ones so offended by the piece.  But no, they actually invited me to come to a morning talk and to chat afterwards, and were completely professional and cordial and made it clear they understood the angle I had taken as a sincere journalistic approach.  But not only did I hear the talk then, but I had gotten a preview the night before in the Twist Suite, which also illustrates a key card BioNano has: a collaboration with Alexander Hoischen

10X Triples Down on Spatial Analysis

10X Genomics last week announced the purchase of ReadCoor, a company that unveiled its 3D spatial sequencing instrument back at AGBT, paying $350M to acquire the Cambridge MA company.  This follows quickly on the heels of 10X purchasing Swedish in situ sequencing company CartaNA for another $41M.  10X already had the Visium spatial transcriptomics product on the market.  So now 10X has three different technologies in the spatial profiling space.